OP0203 IMMUNOPHENOTYPING OF RHEUMATOID ARTHRITIS STRATIFIES FIVE GROUPS THAT HAVE DIFFERENT RESPONSES TO MOLECULAR TARGETED THERAPIES
Authors: S. Kubo, S. Nakayamada, Y. Miyazaki, Y. Fujita, R. Kanda, K. Kusaka, Y. Todoroki, H. Miyata, K. Sonomoto, S. Fukuyo, K. Hanami, Y. Tanaka
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Different molecular targeted therapies affect immune cell phenotypes and signals differently due to their modes of action<sup>[1]</sup>. Theoretically, it is possible to use these drugs based on a stratification of rheumatoid arthritis (RA) patients. However, despite innovations in the treatment of RA, precision medicine with the development and application of personalized treatments by molecular targeted therapy is still far from its achievement. At least, precision medicine by a single biomarker is not known to be possible<sup>[2]</sup>. <h3>Objectives</h3> To investigate the possibility of precision medicine based on the immune phenotype of peripheral blood, we stratified RA patients by comprehensive flow cytometric immunophenotyping and evaluated the response to targeted therapy. <h3>Methods</h3> This study enrolled 96 healthy controls (HC) and 533 bio-naive RA patients with moderate to severe disease activity acording to CDAI. The Human Immunology Project, a NIH/FOCIS-developed flow cytometric immune cell profiling method on T cells, B cells, NK cells, dendritic cells, and monocytes, was used to stratify the patients using cluster analysis (Ward and UMAP methods). Inverse probability weighting with propensity scores was used to control for patient characteristics and CDAI was used to measure remission achievement after 6 months of targeted molecular therapy for each stratified subgroup. <h3>Results</h3> The mean age was 63.5 years old, and the disease activity was CDAI 27.1. In comparison to HC, CD4 T cell differentiation was noticeably affected in RA patients, with elevated effector T cells and effector memory T cells re-expressing CD45RA (TEMRA). Meanwhile, there was no meaningful change in the proportion of Th1, Th17, Treg, and Tfh cells as well as B cells, NK cells, monocytes, and dendritic cells subpopulations. Cluster analysis of the immunophenotypes revealed five main groups of RA patients, with roughly equal numbers of patients in each group. When dimension reduction of their immunophenotypes was performed by UMAP, these groups were clearly separated (Figure 1). One of the five groups had an immunophenotype almost identical to that of healthy controls (cluster 1), two groups were moderately different (clusters 2 and 3), and the last two groups had phenotypes characteristic of RA with little overlap with healthy controls (clusters 4 and 5). These 2 groups were accompanied by a marked increase in TEMRA with increased effector memory T cells (cluster 4) and with increased Th1 (cluster 5). There were few differences in baseline clinical findings such as disease activity and ACPA/RF among the groups. Of note, the clinical efficacy of each targeted therapy was statistically different in each group. In the group with immunophenotypes similar to those of healthy subjects (cluster 1) and the moderately different group (cluster 2), JAK inhibitors and IL-6R antibody treatment were effective, while TNF inhibitors were effective in another moderately different group (cluster 3). CTLA4-Ig and TNF inhibitors were effective in the two groups with phenotypes characteristic of RA (clusters 4 and 5). Immunophenotyping after treatment revealed that the first three groups became comparable to the HC phenotype. However, TEMRA dominancy groups (clusters 4 and 5) remained elevated in TEMRA. Interestingly, CTLA4-Ig decreased the proportion of TEMRA. <h3>Conclusion</h3> RA patients can be stratified into five groups, each of which benefited from different molecular targeted therapies. The increase in CD4 TEMRA in peripheral blood was significant in RA patients, and the proportion was virtually unchanged with treatment. Thus, CD4 TEMRA could be the pathogenic memory cells in RA. Our results may be a milestone in achieving precision medicine. <h3>References</h3> [1]Nakayamada S, Kubo S, et al. Differential effects of biological DMARDs on peripheral immune cell phenotypes in patients with rheumatoid arthritis. Rheumatology (Oxford) 2018; 57(1): 164-74. [2]Lin CMA, et al. Precision medicine: the precision gap in rheumatic disease. Nat Rev Rheumatol 2022; 18(12): 725-33. <h3>Acknowledgements</h3> The author thanks Ms. N. Sakaguchi for the excellent technical assistance, and thanks all medical staff at all participating medical facilities for providing the data. <h3>Disclosure of Interests</h3> Satoshi Kubo Speakers bureau: Eli Lilly, Bristol-Myers, and GlaxoSmithKline, Grant/research support from: Daiichi-Sankyo, Abbvie, Boehringer Ingelheim, and Astellas., Shingo Nakayamada Speakers bureau: Bristol-Myers, AstraZeneca, Pfizer, GlaxoSmithKline, Astellas, Asahi-Kasei, Sanofi, Abbvie, Eisai, Chugai, Gilead, Boehringer Ingelheim, Grant/research support from: Mitsubishi-Tanabe, Yusuke Miyazaki Speakers bureau: Eli Lilly, GlaxoSmithKline, Grant/research support from: GlaxoSmithKline, YUYA FUJITA: None declared, Ryuichiro Kanda: None declared, Katsuhide Kusaka: None declared, Yasuyuki Todoroki: None declared, Hiroko Miyata: None declared, Koshiro Sonomoto: None declared, Shunsuke Fukuyo: None declared, Kentaro Hanami: None declared, Yoshiya Tanaka Speakers bureau: Behringer-Ingelheim, Eli Lilly, Abbvie, Gilead, AstraZeneca, Bristol-Myers, Chugai, Daiichi-Sankyo, Eisai, Pfizer, Mitsubishi-Tanabe, GlaxoSmithKline, Grant/research support from: Asahi-Kasei, Abbvie, Chugai, Eisai, Takeda, Daiichi-Sankyo, Behringer-Ingelheim.